ABSTRACT Islet amyloid formation is a pathological hallmark of type 2 diabetes and is observed in >90% of patients with the disease. These amyloid deposits are associated with -cell apoptosis resulting in -cell mass loss. In the autoimmune disease process of type 1 diabetes, cytokines are responsible for the induction of -cell apoptosis. Studies of the mechanisms of -cell loss have identified the involvement of a number of pro- apoptotic molecules. However, the role of apoptosis repressor with a caspase recruitment domain (ARC), a novel anti-apoptotic protein recently identified in the cell, remains largely unknown. To gai greater insight into the mechanisms of -cell apoptosis, we will determine how ARC interacts with other proteins in the cell to limit apoptosis. These interactions include (a) synergizing wth the anti-apoptotic protein 14-3-3?, (b) inhibiting signaling by the pro-apoptotic protein JNK, an (c) inhibiing signaling pathway molecules activated by TNF-?-, IL-1, and IFN-?. In this application we propose four specific aims to examine the mechanisms by which ARC decreases - cell apoptosis. Specific Aims 1-3 will utilize in vitro approaches. The first two aims primaril address islet amyloid-induced mechanisms, while the third focuses on those induced by cytokines. Specific Aim 4 will be done in vivo to examine the translational relevance of increasing ARC in the cell. Specific Aim 1: To determine if ARC's inhibition of JNK and/or p53 is sufficient to prevent amyloid-induced - cell apoptosis. Specific Aim 2: To determine the role of 14-3-3? in mediating the effect of ARC to reduce amyloid-induced - cell apoptosis. Specific Aim 3: To determine whether ARC prevents cytokine-induced -cell apoptosis and the mechanism(s) by which it does so. Specific Aim 4: To determine in vivo whether increasing ARC expression in cells can safely reduce amyloid- induced -cell loss. For the in vitro studies (Specific Aims 1-3) we will use islets from our transgenic mouse model of islet amyloid, wild type mice and humans as well as an immortalized -cell line. For the in vivo work examining the effects of ARC in cells (Specific Aim 4), we will produce a new transgenic mouse model expressing both human islet amyloid polypeptide (hIAPP) and ARC in its cells. The long-term goal of this work is to define additional targets to prevent or curtail -cell loss, an important component of the diabetes disease process.